Identification of susceptible genes for complex chronic diseases based on disease risk functional SNPs and interaction networks.

Complex chronic diseases are caused by the effects of genetic and environmental factors. Single nucleotide polymorphisms (SNPs), one common type of genetic variations, played vital roles in diseases. We hypothesized that disease risk functional SNPs in coding regions and protein interaction network modules were more likely to contribute to the identification of disease susceptible genes for complex chronic diseases. This could help to further reveal the pathogenesis of complex chronic diseases. Disease risk SNPs were first recognized from public SNP data for coronary heart disease (CHD), hypertension (HT) and type 2 diabetes (T2D). SNPs in coding regions that were classified into nonsense and missense by integrating several SNP functional annotation databases were treated as functional SNPs. Then, regions significantly associated with each disease were screened using random permutations for disease risk functional SNPs. Corresponding to these regions, 155, 169 and 173 potential disease susceptible genes were identified for CHD, HT and T2D, respectively. A disease-related gene product interaction network in environmental context was constructed for interacting gene products of both disease genes and potential disease susceptible genes for these diseases. After functional enrichment analysis for disease associated modules, 5 CHD susceptible genes, 7 HT susceptible genes and 3 T2D susceptible genes were finally identified, some of which had pleiotropic effects. Most of these genes were verified to be related to these diseases in literature. This was similar for disease genes identified from another method proposed by Lee et al. from a different aspect. This research could provide novel perspectives for diagnosis and treatment of complex chronic diseases and susceptible genes identification for other diseases.